Traumatic brain injury (TBI) causes neuronal cell death combined with astroglial proliferation and inflammation associated with activation of microglia. Upregulation of cell cycle proteins occurs after CMS trauma, and appears to contribute to apoptotic cell death of post-mitotic cells such as neurons. It also likely contributes to posttraumatic gliosis and microglial activation. Recent studies in our laboratory have shown significantly increased expression of many cell cycle proteins after TBI or spinal cord injury in rodents, with the proteins co-expressed in neurons showing caspase-3 activation and morphological features of apoptosis. Moreover, in several classical models of caspase-3 dependent apoptosis in primary neuronal cell cultures, injury is associated with up-regulation of many of these same cell cycle proteins. In addition, pilot studies have indicated that inhibition of key cell cycle regulatory pathways reduces injury-induced cell death both in vitro and in vivo. Thus, treatment with a cell cycle inhibitor after TBI in rats markedly reduces lesion volumes and the surrounding glial scar; it also significantly improves motor and cognitive functions following brain injury. The proposed studies are intended to address the following hypotheses: (1) TBI up-regulates key cell cycle constituents at both the mRNA and protein levels in neurons, astrocytes, and microglia; (2) such an up-regulation promotes apoptosis in neurons and proliferation of astrocytes; (3) up-regulation of cell cycle proteins contributes to microglial activation and subsequent release of associated inflammatory factors; and (4) treatment with cell cycle inhibitors is neuroprotective, through mechanisms that include inhibition of the intrinsic caspase pathway in neurons, as well as reduced glial activation and diminished release of microglial mediated inflammatory factors. Specific aims are to demonstrate that: (1) a. TBI causes increased expression of a number of critical cell cycle related genes/proteins, including cyclin D1, CDK4, CDK5 and Rb in both neurons and glia; b. increased protein expression is associated with caspase-dependent apoptosis in neurons, proliferation of astroglia, activation of microglia and facilitated release of microglia-related inflammatory factors; c. cyclin D1 knockout mice show less intense injury-induced pathobiology including neuronal apoptosis, brain lesion, astroglial scar formation, release of microglial associated inflammatory factors, and post-traumatic neurological deficits; (2) a. structurally different cell cycle inhibitors in dose-dependent manner reduce lesion volumes and improve cognitive as well as motor function in two pathobiologically different TBI models in the rat and mouse; b. cell cycle inhibitors decrease cell cycle activation after TBI, thereby reducing subsequent neuronal cell death, reactive gliosis and microglial activation; c. delayed systemic administration of a cell cycle inhibitor, a more clinically relevant paradigm, is neuroprotective.